The present invention relates to the use of 2-alkylpyrrolidines in the treatment of diabetes and pharmaceutical compositions containing these compounds.
Diabetes is characterized by an impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patients. Underlying defects lead to a classification of diabetes into two major groups: type 1 diabetes, or insulin demanding diabetes mellitus (IDDM), which arises when patients lack xcex2-cells producing insulin in their pancreatic glands, and type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with an impaired xcex2-cell function in association with a range of other abnormalities.
Type 1 diabetic patients are currently treated with insulin. The majority of type 2 diabetic patients are treated either with sulfonylureas that stimulate xcex2-cell function, with xcex1-glucosidase inhibitors which decrease carbohydrate uptake from the intestine in association with meals, or with agents that enhance the tissue sensitivity of the patients towards insulin or with insulin. Among the agents applied to enhance tissue sensitivity towards insulin, metformin is a representative example. Examples of xcex1-glucosidase inhibitors are acarbose and voglibose.
Even though sulfonylureas and xcex1-glucosidase inhibitors are widely used in the treatment of NMDDM, this therapy is, in most instances, not satisfactory: Thus, in a large number of NIDDM patients, sulfonylureas and xcex1-glucosidase inhibitors do not suffice to normalize blood sugar levels and the patients are, therefore, at high risk for acquiring diabetic complications. Also, many patients gradually lose the ability to respond to treatment with sulfonylureas and are gradually forced into insulin treatment. This shift of patients from oral hypoglycaemic agents to insulin therapy is usually ascribed to exhaustion of the xcex2-cells in NIDDM patients.
In normals as well as in diabetics, the liver produces glucose in order to avoid hypoglycemia. This glucose production is derived either from the release of glucose from glycogen stores or from gluconeogenesis, which is a de novo intracellular synthesis of glucose. In type 2 diabetes, however, the regulation of hepatic glucose output is poorly controlled and is increased, and may be doubled after an overnight fast. Moreover, in these patients there exists a strong correlation between the increased fasting plasma glucose levels and the rate of hepatic glucose production (reviewed in R. A. De Fronzo: Diabetes 37 (1988), 667-687; A. Consoli: Diabetes Care 15 (1992), 430-441; and J. E. Gerich: Horm.Metab.Res. 26 (1992), 18-21). Similarly, if type 1 diabetes is not properly controlled by insulin treatment, hepatic glucose production, particularly from glycogen, will be increased and result in fasting hyperglycemia.
Since existing forms of therapy of diabetes does not lead to sufficient glycaemic control and therefore are unsatisfying, there is a great demand for novel therapeutic approaches. Since the liver in diabetes is known to have an increased glucose production, compounds inhibiting this activity are highly desirable.
Recently, patents on inhibitors of the liver specific enzyme, glucose-6-phosphatase, which is necessary for the release of glucose from the liver, have been filed, for example German Offenlepunisschrift Nos. 4,202,183 and 4,202,184 and Japanese patent application No. 4-58565. All these known compounds are benzene derivatives.
International patent application having publication No. WO 92/16640 relates to di-, tri- and tetrasaccharides that are substrates or inhibitors of glycosyltransferase and glycosidase enzymes. Some specific compounds mentioned therein are 2,3,4,5-tetrahydroxypiperidine, 3,4,5-trihydroxy-6-methylpiperidine and 3,4-dihydroxy-5-methylpiperidine.
International Patent Application No. WO 92/21657 relates to certain xcfx89-deoxyazapyranoses, e.g. 3,4-dihydroxy-5-methyl-piperidine mentioned in claim 16 thereof. It is stated that these compounds have glucosidase inhibiting properties.
European patent application having publication No. 528,495 A1 relates to a class of azacyclic compounds, i.e. compounds comprising an azacyclic ring system substituted by arylmethyloxy or an arylmethylthio moiety. These compounds may be useful as tachykinin antagonists.
European patent application having publication No. 375,651 A1 relates to 1,4-dideoxy-1,4-imino-L-allitol and derivatives thereof having glycosidase inhibitory activity.
Moreover, scientifically it is well realized that inhibition of glycogen phosphorylase is a suitable target for the treatment of diabetes (Martin et al., 1991; Biochemistry 30: 10101-16; Oikonomakos et al., 1994; Eur. J. Drug Metab. Pharmakokin. 3: 185-92). These groups have used glucose analogs.
European patent application No. 422,307 relates to preparation of N-glycosyl 1,4-dideoxy-1,4-imino-D-arabinitols as xcex1-glycosidase inhibitors. These compounds are said to be useful in the treatment of diabaetes mellitus.
European patent application No. 389,723 relates to the preparation of iminoarabinitol derivatives as xcex1-glucosidase inhibitors.
U.S. Pat. No. 4,973,602 relates to antiviral (2S,3S,4S) pyrrolidines having benzyloxycarbonyl or an optionally substituted alkylphenyl group in the 1-position. In said US patent, (2S,3S,4S)-1-([4-chlorophenyl]methyl-2-hydroxymethyl-3,4-dihydroxypyrrolidine is specifically mentioned.
European patent application No. 367,747 relates to antiviral (2S,3S,4S) pyrrolidines, e.g. (2S,3S,4S)-2-hydroxymethyl-3,4-dihydroxypyrrolidines having methyl, butyl, hexyl, nonyl, propionyl, 2-hydroxyethyl or 5-hydroxypentyl in the 1-position.
European patent application No. 322.395 describes some pyrrolidines and piperidines, which can be used for the treatment of AIDS. Examples of specific compounds mentioned therein are 2-hydroxymethyl-3,4-dihydroxypyrrolidine and the corresponding 1-methyl derivative.
One object of the present invention is to furnish compounds which can be used as medicaments.
A further object of this invention is to furnish compounds which can effectively be used in the treatment of diabetes.
A still further object of this invention is to furnish compounds which can effectively be used as inhibitors of glucose production from the liver.
A further object of this invention is to furnish compounds which can effectively be used as phosphorylase inhibitors.
The present invention relates to compounds of the general formula I stated in the claims below.
Surprisingly, it has been found that the compounds stated in the claims, below, have interesting pharmaco-logical properties. For example, the compounds can be used in the treatment of diabetes. Especially, the compounds are active as inhibitors of glucose production from the liver. Consequently, the compounds can be used for the treatment of the increased plasma glucose levels in diabetics.
Hereinafter, the term alkyl, when used alone or in combination with another moiety, is a straight or branched saturated hydrocarbon chain group which preferably contains not more than 8 carbon atoms, more preferred not more than 4 carbon atoms. Especially preferred alkyl groups are methyl, ethyl, propyl and isopropyl.
The term halogen as used herein refers to chloro, bromo or fluoro, preferably fluoro. Preferably, N-alkylamino is N-methylamino. Preferably, N,N-dialkylamino is N,N-dimethylamino. The term acyl as used herein refers to carbonyl sub-stituted with hydrogen, alkyl or phenyl. Herein, cycloalkyl preferably contains 3-7 carbon atoms, more prefered 3-6 carbon atoms. Alkoxy preferably is methoxy or ethoxy. Alkoxycarbonyl preferably is methoxycarbonyl or ethoxycarbonyl. Aralkyl preferably is benzyl. Trifluoroalkyl preferably is trifluoromethyl or 2,2,2-trifluoroethyl. Alkene preferably contains not more than 8 carbon atoms and preferably is allyl. The term xe2x80x9cone or morexe2x80x9d substituents preferably is 1-3 substituents, most preferred 1.
A subgroup of compounds to be used according to this invention are compounds of formula I wherein the two substituets designated by the symbols R3 and R5 are situated at the same side of the plane formed by the 5 membered nitrogen containing ring, and R4 is situated at the opposite side of the plane formed by the 5 membered nitrogen containing ring. Such compounds are either (2S,3S,4S)-2-alkylpyrrolidines or (2R,3R,4R)-2-alkylpyrrolidines. Among these compounds, the (2R,3R,4R)-2-alkylpyrrolidines are preferred.
Examples of compounds to be used according to this invention are compounds of formula I wherein R1 is alkyl which optionally is substituted with one or more of the following groups: hydroxy, alkoxy, amino, N-alkylamino, N,N-dialkylamino, alkoxycarbonyl, cycloalkyl or optionally substituted phenyl.
Another example of compounds to be used according to this invention are compounds of formula I wherein R1 is phenylalkyl wherein the phenyl moiety optionally is substituted with one or more of the following groups: halogen, hydroxy, alkoxy, trifluoromethyl or cyano.
Another subgroup of compounds to be used according to this invention are compounds of formula I wherein R3 and R4 each are hydroxy, and R5 is hydroxymethyl.
The compounds of formula I may be presented as a mixture of isomers which, if desired, may be resolved into the individual pure enantiomers. This resolution may conveniently be performed by fractional crystallization from various solvents, of the salts of compounds of the formula I with optical active acids or by other methods known per se, for example, chiral column chromatography. This invention includes all isomers, whether resolved or mixtures thereof.
Examples of pharmaceutically acceptable salts are acid addition salts with non-toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
Preferred compounds to be used according to this invention are 3,4-dihydroxy-2-hydroxymethylpyrrolidine, 3,4-dihydroxy-2-hydroxymethyl-1-methylpyrrolidine, 1-cyclopropylmethyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine, 3,4-dihydroxy-2-hydroxymethyl-1-propylpyrrolidine, 1-butyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,3,4-dihydroxy-2-hydroxymethyl-1-(2,2,2-trifluoroethyl)pyrrolidine, 1-benzyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine, 3,4-dihydroxy-2-hydroxymethyl-1-(2-hydroxyethyl)pyrrolidine, 3,4-dihydroxy-2-hydroxymethyl-1-(1,3-dihydroxyprop-2-yl)pyrrolidine, 3,4-dihydroxy-2-hydroxymethyl-1-(2,3-dihydroxyprop-1-yl)pyrrolidine, 1-(2-aminoethyl)-3,4-dihydroxy-2-hydroxymethylpyrrolidine and salts and hydrates thereof, preferably (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethylpyrrolidine, (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-1-methylpyrrolidine, (2R,3R,4R)-1-cyclopropylmethyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine(2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-1-propylpyrrolidine, (2R,3R,4R)-1-butyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine, (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-1-(2,2,2-trifluoroethyl)pyrrolidine, (2R,3R,4R)-1-benzyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine, (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-1-(2-hydroxyethyl)pyrrolidine, (2R,3R,4R)-3,4-hydroxy-2-hydroxymethyl-1-(2,3-hydroxyprop-1-yl)pyrrolidine, (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-1-(1,3-dihydroxyprop-2-yl)pyrrolidine, (2R,3R,4R)-1-(2-aminoethyl)-3,4-dihydroxy-2-hydroxymethylpyrrolidine, (2S,3S,4S)-3,4-dihydroxy-2-hydroxymethylpyrrolidine, (2S,3S,4S)-3,4-dihydroxy-2-hydroxymethyl-1-methylpyrrolidine, (2S,3S,4S)-1-cyclopropylmethyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,(2S,3S,4S)-3,4-dihydroxy-2-hydroxymethyl-1-propylpyrrolidine, (2S,3S,4S)-1-butyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine(2S,3S,4S)-3,4dihydroxy-2-hydroxymethyl-1-(2,2,2-trifluoroethyl)pyrrolidine, (2S,3S,4S)-1-benzyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine, (2S,3S, 4S)-3,4-dihydroxy-2-hydroxymethyl-1-(2-hydroxyethyl)pyrrolidine(2S,3S,4S)-3,4-dihydroxy-2-hydroxymethyl-1-(2,3-dihydroxyprop-1-yl)pyrrolidine, (2S,3S,4S)-3,4-dihydroxy-2-hydroxymethyl-1-(1,3-dihydroxyprop-2-yl)pyrrolidine, (2S,3S,4S)-1-(2-aminoethyl)-3,4-dihydroxy-2-hydroxymethylpyrrolidine and salts and hydrates thereof.
Generally, the compounds of formula I are prepared by methods known per se by the skilled art worker, for example as described in the following. The compounds of formula I can be prepared by joining the C-1 and C-4 of xylose together with nitrogen to form the pyrrolidine ring as described in Tetrahedron 42 (1986), 5685 et seq. A variety of functional groups can be introduced in the compounds prepared as outlined above by methods well known to those skilled in the art.
More specifically, the compounds of formula I can be prepared as follows:
a) Reacting a compound of the general formula II 
wherein R2, R3, R4, and R5 are as defined in the claims below, with an aldehyde in presence of a reducing agent among which sodium cyanoborohydride is preferred, to form a compound of formula I.
b) Reacting a compound of the general formula II 
wherein R2, R3, R4, and R5 are as defined in the claims below, with a compound of the general formula R1Y, wherein R1 is as defined in the claims below, and Y is a leaving group, to form a compound of formula I. The reaction is carried out under alkaline conditions, i.e. in the presence of a base.
The leaving group, Y, may be any suitable leaving group as for example halogen.
c) Reacting a compound of the general formula III 
wherein R1 either is as defined in the claims below or is a readily removable protection group, i.e. benzyl, R2 is as defined in the claims below and R3 and R4 are protected hydroxy, i.e. benzyloxy, with a halogenating agent such as thionyl chloride, thionyl bromide, or diethylaminosulfur trifluoride (DAST) and subsequent removal of the protection groups to form a compound of formula I, wherein R1, R3, and R4 are as defined in the claims below, and R5 is methyl substituted with halogen.
d) Reacting a compound of the general formula IV 
wherein R1 either is as defined in the claims below or is a readily removable protection group, i.e. benzyl, R2 is as defined in the claims below, R3 and R4 are protected hydroxy, i.e. benzyloxy, and X is a leaving group, with a compound of the general formula NHR6R7, wherein the two substituents R6 and R7 may both be alkyl, or one is allyl and the other is hydrogen or together with NH R6 and R7 form phthalimide, and subsequent removal of the protection groups to form the compounds of formula I, wherein R1, R2, R3, and R4 are as defined in the claims below, and R5 is methyl substituted with amino, N-alkylamino, or N,N-dialkylamino.
The leaving group, X, may be any suitable leaving group as for example halogen.
e) Reacting a compound of the general formula I 
wherein R1 and R2 are as defined in the claims below, and one or two of the groups R3 and R4 is hydroxy and the remaining is protected hydroxy, i.e. benzyl, R1 is as defined in the claims below or is a corresponding protected group, with a halogenating agent such as thionyl chloride, thionyl bromide or diethylaminosulfur trifluoride (DAST) and subsequent removal of the protection groups to form a compound of the formula I, wherein R1, R2 and R5 are as defined in the claims below, and R3 and R4 are hydroxy or halogen, but not more than one of R3 and R4 is hydroxy.
Pharmaceutical Compositions
This invention further provides pharmaceutical compositions which comprise at least one compound of formula I or a pharmaceutically acceptable salt thereof in connection with a pharmaceutically acceptable carrier. Such compositions may be in the form of powders, solutions, or suspensions, which may or may not be divided in unit dosage form or in the form of capsules or tablets.
The pharmaceutical compositions of this invention may comprise carriers, diluents, absorption enhancers, tablet disintegrating agents and other ingredients which are conventionally used in the art. The powders and tablets preferably contain from 5 to 99%, more preferred from 10 to 90% of the active ingredient. Examples of solid carriers are magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes and cocoa butter.
Liquid compositions include sterile solutions, suspensions and emulsions suitable for parenteral injection.
The route of administration of the compositions containing a compound of formula I may be any route which effectively transports the active compound to its site of action, the oral or nasal route being preferred.
The regimen for any patient to be treated with the compositions according to the present invention should be determined by those skilled in the art. The daily dose to be administered in therapy can be determined by a physician and will depend on the particular compound employed, on the route of administration and on the age and the condition of the patient. A convenient daily dosage can be less than about 1 g, preferably in the range around 10-200 mg.
The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection.
The features disclosed in the foregoing description and in the following examples and claims may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.